Pharmaceutical compositions based on anticholinergics and endothelin antagonists

ABSTRACT

The present invention relates to novel pharmaceutical compositions based on anticholinergics and endothelin antagonists, processes for preparing them and their use in the treatment of respiratory tract diseases.

[0001] The present invention relates to novel pharmaceuticalcompositions based on anticholinergics and endothelin antagonists,processes for preparing them and their use in the treatment ofrespiratory diseases.

DESCRIPTION OF THE INVENTION

[0002] The present invention relates to novel pharmaceuticalcompositions based on anticholinergics and endothelin antagonists,processes for preparing them and their use in the treatment ofrespiratory diseases.

[0003] Surprisingly, it has been found that an unexpectedly beneficialtherapeutic effect, particularly a synergistic effect can be observed inthe treatment of diseases of the upper or lower respiratory tract,particularly in the treatment of allergic or non-allergic rhinitis, ifone or more, preferably one anticholinergic is or are used together withone or more, preferably one, endothelin antagonist. Thanks to thissynergistic effect the pharmaceutical combinations according to theinvention can be used in lower doses than is the case when theindividual compounds are used in monotherapy in the usual way.

[0004] The effects mentioned above are observed both when the two activesubstances are administered simultaneously in a single active substanceformulation and when they are administered successively in separateformulations. According to the invention, it is preferable if the twoactive substance ingredients are administered simultaneously in a singleformulation.

[0005] Within the scope of the present invention the termanticholinergics 1 denotes salts which are preferably selected from thegroup consisting of tiotropium salts, oxitropium salts and ipratropiumsalts, of which ipratropium salts and tiotropium salts are particularlypreferred. In the abovementioned salts the cations tiotropium,oxitropium and ipratropium are the pharmacologically active ingredients.Within the scope of the present patent application, any reference to theabove cations is indicated by the use of the number 1′. Any reference tocompounds 1 naturally also includes a reference to the ingredients 1′(tiotropium, oxitropium or ipratropium).

[0006] By the salts 1 which may be used within the scope of the presentinvention are meant the compounds which contain, in addition totiotropium, oxitropium or ipratropium, as counter-ion (anion), chloride,bromide, iodide, methanesulphonate or para-toluenesulphonate. Within thescope of the present invention, the methanesulphonate, chloride, bromideand iodide are preferred of all the salts 1, the methanesulphonate andbromide being of particular importance. Salts 1 selected from amongtiotropium bromide, oxitropium bromide and ipratropium bromide are ofoutstanding importance according to the invention. Ipratropium bromideand tiotropium bromide are particularly preferred.

[0007] Within the scope of the present invention the term endothelinantagonists (hereinafter 2) denotes compounds selected from amongtezosentan, bosentan, enrasentan, sixtasentan, T-0201, BMS-193884,K-8794, PD-156123, PD-156707, PD-160874, PD-180988, S-0139 and ZD-1611.Preferred endothelin antagonists 2 within the scope of the presentinvention are those selected from among tezosentan, bosentan,enrasentan, sixtasentan, T-0201 and BMS-193884, the compounds tezosentanand bosentan being particularly preferred according to the invention.

[0008] Any reference to the abovementioned endothelin antagonists 2within the scope of the present invention includes a reference to anypharmacologically acceptable acid addition salts thereof which mayexist. By the physiologically or pharmacologically acceptable acidaddition salts which may be formed from 2 are meant, according to theinvention, pharmaceutically acceptable salts selected from among thesalts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoricacid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid,lactic acid, citric acid, tartaric acid or maleic acid.

[0009] Any reference to the abovementioned endothelin antagonists 2within the scope of the present invention includes a reference to anyalkali metal and alkaline earth metal salts thereof which may exist. Ifthe compounds of formula 2 are present in the form of their basic salts,the sodium or potassium salts are particularly preferred.

[0010] The pharmaceutical combinations of 1 and 2 according to theinvention are preferably administered by parenteral or oral route or byinhalation, the latter being particularly preferred. For oral orparenteral administration the pharmaceutical compositions according tothe invention may be administered in the form of solutions and tablets.For inhalation, as preferred according to the invention, suitableinhalable powders may be used which are packed into suitable capsules(inhalettes) and administered using suitable powder inhalers.Alternatively, the drug may be inhaled by the application of suitableinhalation aerosols. These include inhalation aerosols which containHFA134a, HFA227 or a mixture thereof as propellant gas. The drug mayalso be inhaled using suitable solutions of the pharmaceuticalcombination consisting of 1 and 2.

[0011] In one aspect, therefore, the invention relates to apharmaceutical composition which contains a combination of 1 and 2.

[0012] In another aspect the present invention relates to apharmaceutical composition which contains one or more salts 1 and one ormore compounds 2, optionally in the form of their solvates or hydrates.The active substances may either be combined in a single preparation orcontained in two separate formulations. Pharmaceutical compositionswhich contain the active substances 1 and 2 in a single preparation arepreferred according to the invention.

[0013] In another aspect the present invention relates to apharmaceutical composition which contains, in addition totherapeutically effective quantities of 1 and 2, a pharmaceuticallyacceptable carrier or excipient. In another aspect the present inventionrelates to a pharmaceutical composition which does not contain anypharmaceutically acceptable carrier or excipient in addition totherapeutically effective quantities of 1 and 2.

[0014] The present invention also relates to the use of 1 and 2 forpreparing a pharmaceutical composition containing therapeuticallyeffective quantities of 1 and 2 for treating diseases of the upper orlower respiratory tract, particularly for treating asthma, chronicobstructive pulmonary diseases (COPD) and/or pulmonary hypertension, aswell as allergic and non-allergic rhinitis, provided that treatment withendothelin antagonists is not contraindicated from a therapeutic pointof view, by simultaneous or successive administration. The presentinvention preferably relates to the abovementioned use of 1 and 2 forpreparing a pharmaceutical composition containing therapeuticallyeffective quantities of 1 and 2 for treating asthma and/or chronicobstructive pulmonary diseases (COPD), which may possibly be associatedwith pulmonary hypertension, as well as allergic and non-allergicrhinitis, provided that treatment with endothelin antagonists is notcontraindicated from a therapeutic point of view, by simultaneous orsuccessive administration. Of equal importance is the abovementioned useof 1 and 2 for preparing a pharmaceutical composition containingtherapeutically effective quantities of 1 and 2 for treating pulmonaryhypertension.

[0015] The present invention further relates to the simultaneous orsuccessive use of therapeutically effective doses of the combination ofthe above pharmaceutical compositions 1 and 2 for treating inflammatoryor obstructive diseases of the respiratory tract, particularly asthma,chronic obstructive pulmonary diseases (COPD) and/or pulmonaryhypertension, as well as allergic and non-allergic rhinitis, providedthat treatment with endothelin antagonists is not contraindicated from atherapeutic point of view, by simultaneous or successive administration.The present invention preferably relates to the abovementioned use oftherapeutically effective doses of the combination of the abovementionedpharmaceutical compositions 1 and 2 for treating asthma and/or chronicobstructive pulmonary diseases (COPD), which may possibly be associatedwith pulmonary hypertension, as well as allergic and non-allergicrhinitis, provided that treatment with endothelin antagonists is notcontraindicated from a therapeutic point of view, by simultaneous orsuccessive administration. Of equal importance is the abovementioned useof therapeutically effective doses of the combination of theabovementioned pharmaceutical compositions 1 and 2 for treatingpulmonary hypertension.

[0016] In the active substance combinations of 1 and 2 according to theinvention, ingredients 1 and 2 may be present in the form of theirenantiomers, mixtures of enantiomers or in the form of racemates.

[0017] The proportions in which the two active substances 1 and 2 may beused in the active substance combinations according to the invention arevariable. Active substances 1 and 2 may possibly be present in the formof their solvates or hydrates. Depending on the choice of the compounds1 and 2, the weight ratios which may be used within the scope of thepresent invention vary on the basis of the different molecular weightsof the various compounds and their different potencies. As a rule, thepharmaceutical combinations according to the invention may containcompounds 1 and 2 in ratios by weight ranging from 1:300 to 50:1,preferably from 1:250 to 40:1. In the particularly preferredpharmaceutical combinations which contain ipratropium salt or tiotropiumsalt as compound 1 and a compound selected from among tezosentan,bosentan, enrasentan, sixtasentan, T-0201 and BMS-193884 as endothelinantagonist 2, the weight ratios of 1 to 2 are most preferably in a rangein which ipratropium or tiotropium 1′and 2 are present in proportions of1:150 to 30:1, more preferably from 1:50 to 20:1.

[0018] For example, without restricting the scope of the inventionthereto, preferred combinations of 1 and 2 according to the inventionmay contain ipratropium or tiotropium 1′ and endothelin antagonist 2 inthe following weight ratios: 1:80; 1:79; 1:78; 1:77; 1:76; 1:75; 1:74;1:73; 1:72; 1:71; 1:70; 1:69; 1:68; 1:67; 1:66; 1:65; 1:64; 1:63 1:62;1:61; 1:60; 1:59; 1:58; 1:57; 1:56; 1:55; 1:54; 1:53; 1:52; 1:51; 1:50;1:49; 1:48; 1:47; 1:46; 1:45; 1:44; 1:43; 1:42; 1:41; 1:40; 1:39; 1:38;1:37; 1:36; 1:35; 1:34; 1:33; 1:32; 1:31; 1:30; 1:29; 1:28; 1:27; 1:26;1:25; 1:24; 1:23; 1:22; 1:21; 1:20; 1:19; 1:18; 1:17; 1:16; 1:15; 1:14;1:13; 1:12; 1:11; 1:10; 1:9; 1:8; 1:7; 1:6; 1:5; 1:4; 1:3; 1:2; 1:1;2:1; 3:1; 4:1; 5:1; 6:1; 7:1; 8:1; 9:1; 10:1.

[0019] The pharmaceutical compositions according to the inventioncontaining the combinations of 1 and 2 are normally administered so that1 and 2 are present together in doses of 0.01 to 10,000 μg, preferablyfrom 0.1 to 8000 μg, more preferably from 1 to 5000 μg, better stillfrom 2.5 to 2500 μg, more preferably from 10 to 1500 μg per single dose.For example, combinations of 1 and 2 according to the invention containa quantity of 1′ and endothelin antagonist 2 such that the total dosageper single dose is about 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg,260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg,350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg,440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg,530 μg, 540 μg, 550 μg, 560 μg, 570 μg, 580 μg, 590 μg, 600 μg, 610 μg,620 μg, 630 μg, 640 μg, 650 μg, 660 μg, 670 μg, 680 μg, 690 μg, 700 μg,710 μg, 720 μg, 730 μg, 740 μg, 750 μg, 760 μg, 770 μg, 780 μg, 790 μg,800 μg, 810 μg, 820 μg, 830 μg, 840 μg, 850 μg, 860 μg, 870 μg, 880 μg,890 μg, 900 μg, 910 μg, 920 μg, 930 μg, 940 μg, 950 μg, 960 μg, 970 μg,980 μg, 990 μg, 1000 μg, 1010 μg, 1020 μg, 1030 μg, 1040 μg, 1050 μg,1060 μg, 1070 μg, 1080 μg, 1090 μg, 1100 μg, 1110 μg, 1120 μg, 1130 μg,1140 μg, 1150 μg, 1160 μg, 1170 μg, 1180 μg, 1190 μg, 1200 μg, 1210 μg,1220 μg, 1230 μg, 1240 μg, 1250 μg, 1260 μg, 1270 μg, 1280 μg, 1290 μg,1300 μg, 1310 μg, 1320 μg, 1330 μg, 1340 μg, 1350 μg, 1360 μg, 1370 μg,1380 μg, 1390 μg, 1400 μg, 1410 μg, 1420 μg, 1430 μg, 1440 μg, 1450 μg,1460 μg, 1470 μg, 1480 μg, 1490 μg, 1500 μg, 1510 μg, 1520 μg, 1530 μg,1540 μg, 1550 μg, 1560 μg, 1570 μg, 1580 μg, 1590 μg, 1600 μg, 1610 μg,1620 μg, 1630 μg, 1640 μg, 1650 μg, 1660 μg, 1670 μg, 1680 μg, 1690 μg,1700 μg, 1710 μg, 1720 μg, 1730 μg, 1740 μg, 1750 μg, 1760 μg, 1770 μg,1780 μg, 1790 μg, 1800 μg, 1810 μg, 1820 μg, 1830 μg, 1840 μg, 1850 μg,1860 μg, 1870 μg, 1880 μg, 1890 μg, 1900 μg, 1910 μg, 1920 μg, 1930 μg,1940 μg, 1950 μg, 1960 μg, 1970 μg, 1980 μg, 1990 μg, 2000 μg or thelike. The proposed dosages per single dose suggested above are not to beregarded as being restricted to the numerical values actually stated,but are intended only as examples of dosages. Of course, dosages whichfluctuate around the above values in a range of about +/−5 μg are alsocovered by the values given above by way of example. In these dosageranges the active substances 1′ and 2 may be present in the weightratios specified above.

[0020] For example, without restricting the scope of the inventionthereto, the combinations of 1 and 2 according to the invention maycontain a quantity of tiotropium 1′ and endothelin antagonist 2 suchthat, in each individual dose, 5 μg of 1′ and 100 μg of 2, 5 μg of 1′and 200 μg of 2, 5 μg of 1′ and 300 μg of 2, 5 μg of 1′ and 400 μg of 2,5 μg of 1′ and 500 μg of 2, 5 μg of 1′ and 600 μg of 2, 5 μg of 1′ and700 μg of 2, 5 μg of 1′ and 800 μg of 2, 5 μg of 1′ and 900 μg of 2, 5μg of 1′ and 1000 μg of 2, 5 μg of 1′ and 1500 μg of 2, 5 μg of 1′ and2000 μg of 2, 10 μg of 1′ and 100 μg of 2, 10 μg of 1′ and 200 μg of 2,10 μg of 1′ and 300 μg of 2, 10 μg of 1′ and 400 μg of 2, 10 μg of 1′and 500 μg of 2, 10 μg of 1′ and 600 μg of 2, 10 μg of 1′ and 700 μg of2, 10 μg of 1′ and 800 μg of 2, 10 μg of 1′ and 900 μg of 2, 10 μg of 1′and 1000 μg of 2, 10 μg of 1′ and 1500 μg of 2, 10 μg of 1′ and 2000 μgof 2, 18 μg of 1′ and 100 μg of 2, 18 μg of 1′ and 200 μg of 2, 18 μg of1′ and 300 μg of 2, 18 μg of 1′ and 400 μg of 2, 18 μg of 1′ and 500 μgof 2, 18 μg of 1′ and 600 μg of 2, 18 μg of 1′ and 700 μg of 2, 18 μg of1′ and 800 μg of 2, 18 μg of 1′ and 900 μg of 2, 18 μg of 1′ and 1000 μgof 2, 18 μg of 1′ and 1500 μg of 2, 18 μg of 1′ and 2000 μg of 2, 20 μgof 1′ and 100 μg of 2, 20 μg of 1′ and 200 μg of 2, 20 μg of 1′ and 300μg of 2, 20 μg of 1′ and 400 μg of 2, 20 μg of 1′ and 500 μg of 2, 20 μgof 1′ and 600 μg of 2, 20 μg of 1′ and 700 μg of 2, 20 μg of 1′ and 800μg of 2, 20 μg of 1′ and 900 μg of 2, 20 μg of 1′ and 1000 μg of 2, 20μg of 1′ and 1500 μg of 2, 20 μg of 1′ and 2000 μg of 2, 36 μg of 1′ and100 μg of 2, 36 μg of 1′ and 200 μg of 2, 36 μg of 1′ and 300 μg of 2,36 μg of 1′ and 400 μg of 2, 36 μg of 1′ and 500 μg of 2, 36 μg of 1′and 600 μg of 2, 36 μg of 1′ and 700 μg of 2, 36 μg of 1′ and 800 μg of2, 36 μg of 1′ and 900 μg of 2, 36 μg of 1′ and 1000 μg of 2, 36 μg of1′ and 1500 μg of 2, 36 μg of 1′ and 2000 μg of 2, 40 μg of 1′ and 100μg of 2, 40 μg of 1′ and 200 μg of 2, 40 μg of 1′ and 300 μg of 2, 40 μgof 1′ and 400 μg of 2, 40 μg of 1′ and 500 μg of 2 or40 μg of 1′ and 600μg of 2, 40 μg of 1′ and 700 μg of 2, 40 μg of 1′ and 800 μg of 2, 40 μgof 1′ and 900 μg of 2, 40 μg of 1′ and 1000 μg of 2, 40 μg of 1′ and1500 μg of 2, 40 μg of 1′ and 200 μg of 2 are administered.

[0021] If the active substance combination in which 1 denotes tiotropiumbromide is used as the preferred combination of 1 and 2 according to theinvention, the quantities of active substance 1′ and 2 administered persingle dose mentioned by way of example correspond to the followingquantities of 1 and 2 administered per single dose: 6, μg of 1 and 100μg of 2, 6 μg of 1 and 200 μg of 2, 6 μg of 1 and 300 μg of 2, 6 μg of 1and 400 μg of 2, 6 μg of 1 and 500 μg of 2, 6 μg of 1 and 600 μg of 2, 6μg of 1 and 700 μg of 2, 6 μg of 1 and 800 μg of 2, 6 μg of 1 and 900 μgof 2, 6 μg of 1 and 1000 μg of 2, 6 μg of 1 and 1500 μg of 2, 6 μg of 1and 2000 μg of 2, 12 μg of 1 and 100 μg of 2, 12 μg of 1 and 200 μg of2, 12 μg of 1 and 300 μg of 2, 12 μg of 1 and 400 μg of 2, 12 μg of 1and 500 μg of 2, 12 μg of 1 and 600 μg of 2, 12 μg of 1 and 700 μg of 2,12 μg of 1 and 800 μg of 2, 12 μg of 1 and 900 μg of 2, 12 μg of 1 and1000 μg of 2, 12 μg of 1 and 1500 μg of 2, 12 μg of 1 and 2000 μg of 2,21.7 μg of 1 and 100 μg of 2, 21.7 μg of 1 and 200 μg of 2, 21.7 μg of 1and 300 μg of 2, 21.7 μg of 1 and 400 μg of 2, 21.7 μg of 1 and 500 μgof 2, 21.7 μg of 1 and 600 μg of 2, 21.7 μg of 1 and 700 μg of 2, 21.7μg of 1 and 800 μg of 2, 21.7 μg of 1 and 900 μg of 2, 21.7 μg of 1 and1000 μg of 2,21.7 μg of 1 and 1500 μg of 2, 21.7 μg of 1 and 2000 μg of2, 24.1, μg of 1 and 100 μg of 2, 24.1, μg of 1 and 200 μg of 2, 24.1,μg of 1 and 300 μg of 2, 24.1, μg of 1 and 400 μg of 2, 24.1, μg of 1and 500 μg of 2, 24.1 μg of 1 and 600 μg of 2, 24.1 μg of 1 and 700 μgof 2, 24.1, μg of 1 and 800 μg of 2, 24.1, μg of 1 and 900 μg of 2, 24.1μg of 1 and 1000 μg of 2, 24.1 μg of 1 and 1500 μg of 2, 24.1, μg of 1and 2000 μg of 2, 43.3 μg of 1 and 100 μg of 2, 43.3 μg of 1 and 200 μgof 2, 43.3 μg of 1 and 300 μg of 2, 43.3 μg of 1 and 400 μg of 2, 43.3μg of 1 and 500 μg of 2, 43.3, μg of 1 and 600 μg of 2, 43.3 μg of 1 and700 μg of 2, 43.3 μg of 1 and 800 μg of 2, 43.3 μg of 1 and 900 μg of 2,43.3 μg of 1 and 1000 μg of 2, 43.3, μg of 1 and 1500 μg of 2, 43.3 μgof 1 and 2000 μg of 2, 48.1, μg of 1 and 100 μg of 2, 48.1 μg of 1 and200 μg of 2, 48.1 μg of 1 and 300 μg of 2, 48.1, μg of 1 and 400 μg of2, 48.1 μg of 1 and 500 μg of 2, 48.1 μg of 1 and 600 μg of 2, 48.1 μgof 1 and 700 μg of 2, 48.1 μg of 1 and 800 μg of 2, 48.1 μg of 1 and 900μg of 2, 48.1 μg of 1 and 1000 μg of 2, 48.1 μg of 1 and 1500 μg of 2 or48.1 μg of 1 and 2000 μg of 2.

[0022] If the active substance combination in which 1 is tiotropiumbromide monohydrate is used as the preferred combination of 1 and 2according to the invention, the quantities of 1′ and 2 administered persingle dose specified by way of example hereinbefore correspond to thefollowing quantities of 1 and 2 administered per single dose: 6.2 μg of1 and 100 μg of 2, 6.2 μg of 1 and 200 μg of 2, 6.2 μg of 1 and 300 μgof 2, 6.2 μg of 1 and 400 μg of 2, 6.2 μg of 1 and 500 μg of 2, 6.2 μgof 1 and 600 μg of 2, 6.2 μg of 1 and 700 μg of 2, 6.2 μg of 1 and 800μg of 2, 6.2 μg of 1 and 900 μg of 2, 6.2 μg of 1 and 1000 μg of 2, 6.2μg of 1 and 1500 μg of 2, 6.2 μg of 1 and 2000 μg of 2, 12.5 μg of 1 and100 μg of 2, 12.5 μg of 1 and 200 μg of 2, 12.5 μg of 1 and 300 μg of 2,12.5 μg of 1 and 400 μg of 2, 12.5 μg of 1 and 500 μg of 2, 12.5 μg of 1and 600 μg of 2, 12.5 μg of 1 and 700 μg of 2, 12.5 μg of 1 and 800 μgof 2, 12.5 μg of 1 and 900 μg of 2, 12.5 μg of 1 and 1000 μg of 2, 12.5μg of 1 and 1500 μg of 2, 12.5 μg of 1 and 2000 μg of 2, 22.5 μg of 1and 100 μg of 2, 22.5 μg of 1 and 200 μg of 2, 22.5 μg of 1 and 300 μgof 2, 22.5 μg of 1 and 400 μg of 2, 22.5 μg of 1 and 500 μg of 2, 22.5μg of 1 and 600 μg of 2, 22.5 μg of 1 and 700 μg of 2, 22.5 μg of 1 and800 μg of 2, 22.5 μg of 1 and 900 μg of 2, 22.5 μg of 1 and 1000 μg of2, 22.5 μg of 1 and 1500 μg of 2, 22.5 μg of 1 and 2000 μg of 2, 25 μgof 1 and 100 μg of 2, 25 μg of 1 and 200 μg of 2, 25 μg of 1 and 300 μgof 2, 25 μg of 1 and 400 μg of 2, 25 μg of 1 and 500 μg of 2, 25 μg of 1and 600 μg of 2, 25 μg of 1 and 700 μg of 2, 25 μg of 1 and 800 μg of 2,25 μg of 1 and 900 μg of 2, 25 μg of 1 and 1000 μg of 2, 25 μg of 1 and1500 μg of 2, 25 μg of 1 and 2000 μg of 2, 45 μg of 1 and 100 μg of 2,45 μg of 1 and 200 μg of 2, 45 μg of 1 and 300 μg of 2, 45 μg of 1 and400 μg of 2, 45 μg of 1 and 500 μg of 2, 45 μg of 1 and 600 μg of 2, 45μg of 1 and 700 μg of 2, 45 μg of 1 and 800 μg of 2, 45 μg of 1 and 900μg of 2, 45 μg of 1 and 1000 μg of 2, 45 μg of 1 and 1500 μg of 2, 45 μgof 1 and 2000 μg of 2, 50 μg of 1 and 100 μg of 2, 50 μg of 1 and 200 μgof 2, 50 μg of 1 and 300 μg of 2, 50 μg of 1 and 400 μg of 2, 50 μg of 1and 500 μg of 2, 50 μg of 1 and 600 μg of 2, 50 μg of 1 and 700 μg of 2,50 μg of 1 and 800 μg of 2, 50 μg of 1 and 900 μg of 2, 50 μg of 1 and1000 μg of 2, 50 μg of 1 and 1500 μg of 2 or 50 μg of 1 and 2000 μg of2.

[0023] The active substance combinations of 1 and 2 according to theinvention are preferably administered by inhalation or by nasalapplication. For this purpose, ingredients 1 and 2 have to be madeavailable in inhalable forms. Inhalable preparations include inhalablepowders, propellant-containing metering aerosols or propellant-freeinhalable solutions. Inhalable powders according to the inventioncontaining the combination of active substances 1 and 2 may consist ofthe active substances on their own or of a mixture of the activesubstances with physiologically acceptable excipients. Within the scopeof the present invention, the term propellant-free inhalable solutionsalso includes concentrates or sterile inhalable solutions ready for use.The preparations according to the invention may contain the combinationof active substances 1 and 2 either together in one formulation or intwo separate formulations. These formulations which may be used withinthe scope of the present invention are described in more detail in thenext part of the specification.

[0024] A) Inhalable Powder Containing the Combinations of ActiveSubstances 1 and 2 According to the Invention:

[0025] The inhalable powders according to the invention may contain 1and 2 either on their own or in admixture with suitable physiologicallyacceptable excipients.

[0026] If the active substances 1 and 2 are present in admixture withphysiologically acceptable excipients, the following physiologicallyacceptable excipients may be used to prepare these inhalable powdersaccording to the invention:

[0027] monosaccharides (e.g. glucose or arabinose), disaccharides (e.g.lactose, saccharose, maltose), oligo- and polysaccharides (e.g.dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g.sodium chloride, calcium carbonate) or mixtures of these excipients withone another. Preferably, mono- or disaccharides are used, while the useof lactose or glucose is preferred, particularly, but not exclusively,in the form of their hydrates. For the purposes of the invention,lactose is the particularly preferred excipient, while lactosemonohydrate is most particularly preferred.

[0028] Within the scope of the inhalable powders according to theinvention the excipients have a maximum average particle size of up to250 μm, preferably between 10 and 150 μm, most preferably between 15 and80 μm. It may sometimes seem appropriate to add finer excipientfractions with an average particle size of 1 to 9 μm to the excipientsmentioned above. These finer excipients are also selected from the groupof possible excipients listed hereinbefore. Finally, in order to preparethe inhalable powders according to the invention, micronised activesubstance 1 and 2, preferably with an average particle size of 0.5 to 10μm, more preferably from 1 to 5 μm, is added to the excipient mixture.Processes for producing the inhalable powders according to the inventionby grinding and micronising and by finally mixing the ingredientstogether are known from the prior art. The inhalable powders accordingto the invention may be prepared and administered either in the form ofa single powder mixture which contains both 1 and 2 or in the form ofseparate inhalable powders which contain only 1 or 2.

[0029] The inhalable powders according to the invention may beadministered using inhalers known from the prior art. Inhalable powdersaccording to the invention which contain a physiologically acceptableexcipient in addition to 1 and 2 may be administered, for example, bymeans of inhalers which deliver a single dose from a supply using ameasuring chamber as described in U.S. Pat. No. 4,570,630 A, or by othermeans as described in DE 36 25 685 A. The inhalable powders according tothe invention which contain 1 and 2 optionally combined with aphysiologically acceptable excipient may be administered for examplewith an inhaler known by the name Turbuhaler®, for example with inhalersas disclosed in EP 237507 A, for example. Preferably, the inhalablepowders according to the invention which contain physiologicallyacceptable excipient in addition to 1 and 2 are packed into capsules (toproduce so-called inhalettes) which are used in inhalers as described,for example, in WO 94/28958.

[0030] A particularly preferred inhaler for administering thepharmaceutical combination according to the invention in inhalettes isshown in FIG. 1.

[0031] This inhaler (Handyhaler) for inhaling powdered pharmaceuticalcompositions from capsules is characterised by a housing 1 containingtwo windows 2, a deck 3 in which there are air inlet ports and which isprovided with a screen 5 secured via a screen housing 4, an inhalationchamber 6 connected to the deck 3 on which there is a push button 9provided with two sharpened pins 7 and movable counter to a spring 8,and a mouthpiece 12 which is connected to the housing 1, the deck 3 anda cover 11 via a spindle 10 to enable it to be flipped open or shut.

[0032] If the inhalable powders according to the invention are packedinto capsules (inhalers) for the preferred use described above, thequantities packed into each capsule should be 1 to 30 mg, preferably 3to 20 mg, more particularly 5 to 10 mg of inhalable powder per capsule.These capsules contain, according to the invention, either together orseparately, the doses of 1′ and 2 mentioned hereinbefore for each singledose.

[0033] B) Propellant Gas-driven Inhalation Aerosols Containing theCombinations of Active Substances 1 and 2 According to the Invention:

[0034] Inhalation aerosols containing propellant gas according to theinvention may contain substances 1 and 2 dissolved in the propellant gasor in dispersed form. 1 and 2 may be present in separate formulations orin a single preparation, in which 1 and 2 are either both dissolved,both dispersed or only one component is dissolved and the other isdispersed. The propellant gases which may be used to prepare theinhalation aerosols according to the invention are known from the priorart. Suitable propellant gases are selected from among hydrocarbons suchas n-propane, n-butane or isobutane and halohydrocarbons such asfluorinated derivatives of methane, ethane, propane, butane,cyclopropane or cyclobutane. The propellant gases mentioned above may beused on their own or in mixtures thereof. Particularly preferredpropellant gases are halogenated alkane derivatives selected from TG134a(1,1,1,2-tetrafluoroethane) and TG227(1,1,1,2,3,3,3-heptafluoropropane)and mixtures thereof.

[0035] The propellant-driven inhalation aerosols according to theinvention may also contain other ingredients such as co-solvents,stabilisers, surfactants, antioxidants, lubricants and pH adjusters. Allthese ingredients are known in the art.

[0036] The inhalation aerosols containing propellant gas according tothe invention may contain up to 5 wt.-% of active substance 1 and/or 2.Aerosols according to the invention contain, for example, 0.002 to 5wt.-%, 0.01 to 3 wt.-%, 0.015 to 2 wt.-%, 0.1 to 2 wt.-%, 0.5 to 2 wt.-%or 0.5 to 1.5 wt.-% of active substance 1 and/or 2. If the activesubstances 1 and/or 2 are present in dispersed form, the particles ofactive substance preferably have an average particle size of up to 10μm, preferably from 0.1 to 5 μm, more preferably from 1 to 5 μm.

[0037] The propellant-driven inhalation aerosols according to theinvention mentioned above may be administered using inhalers known inthe art (MDls=metered dose inhalers). Accordingly, in another aspect,the present invention relates to pharmaceutical compositions in the formof propellant-driven aerosols as hereinbefore described combined withone or more inhalers suitable for administering these aerosols. Inaddition, the present invention relates to inhalers which arecharacterised in that they contain the propellant gas-containingaerosols described above according to the invention. The presentinvention also relates to cartridges which when fitted with a suitablevalve can be used in a suitable inhaler and which contain one of theabove-mentioned propellant gas-containing inhalation aerosols accordingto the invention. Suitable cartridges and methods of filling thesecartridges with the inhalable aerosols containing propellant gasaccording to the invention are known from the prior art.

[0038] C) Propellant-free Inhalable Solutions or Suspensions Containingthe Combinations of Active Substances 1 and 2 According to theInvention:

[0039] It is particularly preferred to use the active substancecombination according to the invention in the form of propellant-freeinhalable solutions and suspensions. The solvent used may be an aqueousor alcoholic, preferably an ethanolic solution. The solvent may be wateron its own or a mixture of water and ethanol. The relative proportion ofethanol compared with water is not limited but the maximum is up to 70percent by volume, more particularly up to 60 percent by volume and mostpreferably up to 30 percent by volume. The remainder of the volume ismade up of water. The solutions or suspensions containing 1 and 2,separately or together, are adjusted to a pH of 2 to 7, preferably 2 to5 using suitable acids. The pH may be adjusted using acids selected frominorganic or organic acids. Examples of suitable inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/orphosphoric acid. Examples of particularly suitable organic acids includeascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,succinic acid, fumaric acid, acetic acid, formic acid and/or propionicacid etc. Preferred inorganic acids are hydrochloric and sulphuricacids. It is also possible to use the acids which have already formed anacid addition salt with one of the active substances. Of the organicacids, ascorbic acid, fumaric acid and citric acid are preferred. Ifdesired, mixtures of the above acids may be used, particularly in thecase of acids which have other properties in addition to theiracidifying qualities, e.g. as flavourings, antioxidants or complexingagents, such as citric acid or ascorbic acid, for example. According tothe invention, it is particularly preferred to use hydrochloric acid toadjust the pH.

[0040] According to the invention, the addition of editic acid (EDTA) orone of the known salts thereof, sodium edetate, as stabiliser orcomplexing agent is unnecessary in the present formulation. Otherembodiments may contain this compound or these compounds. In a preferredembodiment the content based on sodium edetate is less than 100 mg/100ml, preferably less than 50 mg/100 ml, more preferably less than 20mg/100 ml. Generally, inhalable solutions in which the content of sodiumedetate is from 0 to 10 mg/100 ml are preferred.

[0041] Co-solvents and/or other excipients may be added to thepropellant-free inhalable solutions according to the invention.Preferred co-solvents are those which contain hydroxyl groups or otherpolar groups, e.g. alcohols—particularly isopropyl alcohol,glycols—particularly propyleneglycol, polyethyleneglycol,polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols andpolyoxyethylene fatty acid esters. The terms excipients and additives inthis context denote any pharmacologically acceptable substance which isnot an active substance but which can be formulated with the activesubstance or substances in the pharmacologically suitable solvent inorder to improve the qualitative properties of the active substanceformulation. Preferably, these substances have no pharmacological effector, in connection with the desired therapy, no appreciable or at leastno undesirable pharmacological effect. The excipients and additivesinclude, for example, surfactants such as soya lecithin, oleic acid,sorbitan esters, such as polysorbates, polyvinylpyrrolidone, otherstabilisers, complexing agents, antioxidants and/or preservatives whichguarantee or prolong the shelf life of the finished pharmaceuticalformulation, flavourings, vitamins and/or other additives known in theart. The additives also include pharmacologically acceptable salts suchas sodium chloride as isotonic agents.

[0042] The preferred excipients include antioxidants such as ascorbicacid, for example, provided that it has not already been used to adjustthe pH, vitamin A, vitamin E, tocopherols and similar vitamins andprovitamins occurring in the human body. Preservatives may be used toprotect the formulation from contamination with pathogens. Suitablepreservatives are those which are known in the art, particularly cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoatessuch as sodium benzoate in the concentration known from the prior art.

[0043] The preservatives mentioned above are preferably present inconcentrations of up to 50 mg/100 ml, more preferably between 5 and 20mg/100 ml.

[0044] Preferred formulations contain, in addition to the solvent waterand the combination of active substances 1 and 2, only benzalkoniumchloride and sodium edetate. In another preferred embodiment, no sodiumedetate is present.

[0045] The propellant-free inhalable solutions according to theinvention are administered in particular using inhalers of the kindwhich are capable of nebulising a small amount of a liquid formulationin the therapeutic dose within a few seconds to produce an aerosolsuitable for therapeutic inhalation. Within the scope of the presentinvention, preferred inhalers are those in which a quantity of less than100 μL, preferably less than 50 μL, more preferably between 10 and 30 μLof active substance solution can be nebulised in preferably one sprayaction to form an aerosol with an average particle size of less than 20μm, preferably less than 10 μm, in such a way that the inhalable part ofthe aerosol corresponds to the therapeutically effective quantity.

[0046] An apparatus of this kind for propellant-free delivery of ametered quantity of a liquid pharmaceutical composition for inhalationis described for example in International Patent Application WO 91/14468and also in WO 97/12687 (cf. in particular FIGS. 6a and 6 b). Thenebulisers (devices) described therein are known by the name Respimat®.

[0047] This nebuliser (Respimat®) can advantageously be used to producethe inhalable aerosols according to the invention containing thecombination of active substances 1 and 2. Because of its cylindricalshape and handy size of less than 9 to 15 cm long and 2 to 4 cm wide,this device can be carried at all times by the patient. The nebulisersprays a defined volume of pharmaceutical formulation using highpressures through small nozzles so as to produce inhalable aerosols. Thepreferred atomiser essentially consists of an upper housing part, a pumphousing, a nozzle, a locking mechanism, a spring housing, a spring and astorage container, characterised by

[0048] a pump housing which is secured in the upper housing part andwhich comprises at one end a nozzle body with the nozzle or nozzlearrangement,

[0049] a hollow plunger with valve body,

[0050] a power takeoff flange in which the hollow plunger is secured andwhich is located in the upper housing part,

[0051] a locking mechanism situated in the upper housing part,

[0052] a spring housing with the spring contained therein, which isrotatably mounted on the upper housing part by means of a rotarybearing,

[0053] a lower housing part which is fitted onto the spring housing inthe axial direction.

[0054] The hollow plunger with valve body corresponds to a devicedisclosed in WO 97/12687. It projects partially into the cylinder of thepump housing and is axially movable within the cylinder. Reference ismade in particular to FIGS. 1 to 4, especially FIG. 3, and the relevantparts of the description. The hollow plunger with valve body exerts apressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa(about 100 to 600 bar) on the fluid, the measured amount of activesubstance solution, at its high pressure end at the moment when thespring is actuated. Volumes of 10 to 50 microlitres are preferred, whilevolumes of 10 to 20 microlitres are particularly preferred and a volumeof 15 microlitres per spray is most particularly preferred.

[0055] The valve body is preferably mounted at the end of the hollowplunger facing the valve body.

[0056] The nozzle in the nozzle body is preferably microstructured, i.e.produced by microtechnology. Microstructured valve bodies are disclosedfor example in WO-94/07607; reference is hereby made to the contents ofthis specification, particularly FIG. 1 therein and the associateddescription.

[0057] The valve body consists for example of two sheets of glass and/orsilicon firmly joined together, at least one of which has one or moremicrostructured channels which connect the nozzle inlet end to thenozzle outlet end. At the nozzle outlet end there is at least one roundor non-round opening 2 to 10 microns deep and 5 to 15 microns wide, thedepth preferably being 4.5 to 6.5 microns while the length is preferably7 to 9 microns.

[0058] In the case of a plurality of nozzle openings, preferably two,the directions of spraying of the nozzles in the nozzle body may extendparallel to one another or may be inclined relative to one another inthe direction of the nozzle opening. In a nozzle body with at least twonozzle openings at the outlet end the directions of spraying may be atan angle of 20 to 160° to one another, preferably 60 to 150° mostpreferably 80 to 100°. The nozzle openings are preferably arranged at aspacing of 10 to 200 microns, more preferably at a spacing of 10 to 100microns, most preferably 30 to 70 microns. Spacings of 50 microns aremost preferred. The directions of spraying will therefore meet in thevicinity of the nozzle openings.

[0059] The liquid pharmaceutical preparation strikes the nozzle bodywith an entry pressure of up to 600 bar, preferably 200 to 300 bar, andis atomised into an inhalable aerosol through the nozzle openings. Thepreferred particle or droplet sizes of the aerosol are up to 20 microns,preferably 3 to 10 microns.

[0060] The locking mechanism contains a spring, preferably a cylindricalhelical compression spring, as a store for the mechanical energy. Thespring acts on the power takeoff flange as an actuating member themovement of which is determined by the position of a locking member. Thetravel of the power takeoff flange is precisely limited by an upper andlower stop. The spring is preferably biased, via a power step-up gear,e.g. a helical thrust gear, by an external torque which is produced whenthe upper housing part is rotated counter to the spring housing in thelower housing part. In this case, the upper housing part and the powertakeoff flange have a single or multiple V-shaped gear.

[0061] The locking member with engaging locking surfaces is arranged ina ring around the power takeoff flange. It consists, for example, of aring of plastic or metal which is inherently radially elasticallydeformable. The ring is arranged in a plane at right angles to theatomiser axis. After the biasing of the spring, the locking surfaces ofthe locking member move into the path of the power takeoff flange andprevent the spring from relaxing. The locking member is actuated bymeans of a button. The actuating button is connected or coupled to thelocking member. In order to actuate the locking mechanism, the actuatingbutton is moved parallel to the annular plane, preferably into theatomiser; this causes the deformable ring to deform in the annual plane.Details of the construction of the locking mechanism are given in WO97/20590.

[0062] The lower housing part is pushed axially over the spring housingand covers the mounting, the drive of the spindle and the storagecontainer for the fluid.

[0063] When the atomiser is actuated the upper housing part is rotatedrelative to the lower housing part, the lower housing part taking thespring housing with it. The spring is thereby compressed and biased bymeans of the helical thrust gear and the locking mechanism engagesautomatically. The angle of rotation is preferably a whole-numberfraction of 360 degrees, e.g. 180 degrees. At the same time as thespring is biased, the power takeoff part in the upper housing part ismoved along by a given distance, the hollow plunger is withdrawn insidethe cylinder in the pump housing, as a result of which some of the fluidis sucked out of the storage container and into the high pressurechamber in front of the nozzle.

[0064] If desired, a number of exchangeable storage containers whichcontain the fluid to be atomised may be pushed into the atomiser oneafter another and used in succession. The storage container contains theaqueous aerosol preparation according to the invention.

[0065] The atomising process is initiated by pressing gently on theactuating button. As a result, the locking mechanism opens up the pathfor the power takeoff member. The biased spring pushes the plunger intothe cylinder of the pump housing. The fluid leaves the nozzle of theatomiser in atomised form.

[0066] Further details of construction are disclosed in PCT ApplicationsWO 97/12683 and WO 97/20590 to which reference is hereby made.

[0067] The components of the atomiser (nebuliser) are made of a materialwhich is suitable for its purpose. The housing of the atomiser and, ifits operation permits, other parts as well are preferably made ofplastics, e.g. by injection moulding. For medicinal purposes,physiologically safe materials are used.

[0068]FIGS. 2a/b attached to this patent application, which areidentical to FIGS. 6a/b of WO 97/12687, show the nebuliser (Respimat®)which can advantageously be used for inhaling the aqueous aerosolpreparations according to the invention.

[0069]FIG. 2a shows a longitudinal section through the atomiser with thespring biased while FIG. 2b shows a longitudinal section through theatomiser with the spring relaxed.

[0070] The upper housing part (51) contains the pump housing (52) on theend of which is mounted the holder (53) for the atomiser nozzle. In theholder is the nozzle body (54) and a filter (55). The hollow plunger(57) fixed in the power takeoff flange (56) of the locking mechanismprojects partially into the cylinder of the pump housing. At its end thehollow plunger carries the valve body (58). The hollow plunger is sealedoff by means of the seal (59). Inside the upper housing part is the stop(60 ) on which the power takeoff flange abuts when the spring isrelaxed. On the power takeoff flange is the stop (61) on which the powertakeoff flange abuts when the spring is biased. After the biasing of thespring the locking member (62) moves between the stop (61) and a support(63) in the upper housing part. The actuating button (64) is connectedto the locking member. The upper housing part ends in the mouthpiece(65) and is sealed off by means of the protective cover (66) which canbe placed thereon.

[0071] The spring housing (67) with compression spring (68) is rotatablymounted on the upper housing part by means of the snap-in lugs (69) androtary bearing. The lower housing part (70) is pushed over the springhousing. Inside the spring housing is the exchangeable storage container(71) for the fluid (72) which is to be atomised. The storage containeris sealed off by the stopper (73) through which the hollow plungerprojects into the storage container and is immersed at its end in thefluid (supply of active substance solution).

[0072] The spindle (74) for the mechanical counter is mounted in thecovering of the spring housing. At the end of the spindle facing theupper housing part is the drive pinion (75). The slider (76) sits on thespindle.

[0073] The nebuliser described above is suitable for nebulising theaerosol preparations according to the invention to produce an aerosolsuitable for inhalation.

[0074] If the formulation according to the invention is nebulised usingthe method described above (Respimat®) the quantity delivered shouldcorrespond to a defined quantity with a tolerance of not more than 25%,preferably 20% of this amount in at least 97%, preferably at least 98%of all operations of the inhaler (spray actuations). Preferably, between5 and 30 mg of formulation, most preferably between 5 and 20 mg offormulation are delivered as a defined mass on each actuation.

[0075] However, the formulation according to the invention may also benebulised by means of inhalers other than those described above, e.g.jet stream inhalers or other stationary nebulisers.

[0076] Accordingly, in a further aspect, the invention relates topharmaceutical formulations in the form of propellant-free inhalablesolutions or suspensions as described above combined with a devicesuitable for administering these formulations, preferably in conjunctionwith the Respimat®. Preferably, the invention relates to propellant-freeinhalable solutions or suspensions characterised by the combination ofactive substances 1 and 2 according to the invention in conjunction withthe device known by the name Respimat®. In addition, the presentinvention relates to the above-mentioned devices for inhalation,preferably the Respimat®, characterised in that they contain thepropellant-free inhalable solutions or suspensions according to theinvention as described hereinbefore.

[0077] Inhalable solutions which contain the active substances 1 and 2in a single preparation are preferred according to the invention. Theterm preparation also includes those which contain both ingredients 1and 2 in two-chamber cartridges as disclosed for example in WO 00/23037.Reference is hereby made to this publication in its entirety.

[0078] The propellant-free inhalable solutions or suspensions accordingto the invention may take the form of concentrates or sterile inhalablesolutions or suspensions ready for use, as well as the above-mentionedsolutions and suspensions designed for use in a Respimat®. Formulationsready for use may be produced from the concentrates, for example, by theaddition of isotonic saline solutions. Sterile formulations ready foruse may be administered using energy-operated fixed or portablenebulisers which produce inhalable aerosols by means of ultrasound orcompressed air by the Venturi principle or other principles.

[0079] Accordingly, in another aspect, the present invention relates topharmaceutical compositions in the form of propellant-free inhalablesolutions or suspensions as described hereinbefore which take the formof concentrates or sterile formulations ready for use, combined with adevice suitable for administering these solutions, characterised in thatthe device is an energy-operated free-standing or portable nebuliserwhich produces inhalable aerosols by means of ultrasound or compressedair by the Venturi principle or other methods.

[0080] The Examples which follow serve to illustrate the presentinvention in more detail without restricting the scope of the inventionto the following embodiments by way of example.

[0081] Starting Materials

[0082] Tiotropium Bromide:

[0083] The tiotropium bromide used in the following formulationsexamples may be obtained as described in European Patent Application 418716 A1.

[0084] In order to prepare the inhalable powders according to theinvention, crystalline tiotropium bromide monohydrate may also be used.This crystalline tiotropium bromide monohydrate may be obtained by themethod described below.

[0085] 15.0 kg of tiotropium bromide are placed in 25.7 kg of water in asuitable reaction vessel. The mixture is heated to 80-90° C. and stirredat constant temperature until a clear solution is formed. Activatedcharcoal (0.8 kg) moistened with water is suspended in 4.4 kg of water,this mixture is added to the solution containing the tiotropium bromideand the resulting mixture is rinsed with 4.3 kg of water. The mixturethus obtained is stirred for at least 15 minutes at 80-90° C. and thenfiltered through a heated filter into an apparatus preheated to anexternal temperature of 70° C. The filter is rinsed with 8.6 kg ofwater. The contents of the apparatus are cooled at 3-5° C. for every 20minutes to a temperature of 20-25° C. The apparatus is cooled further to10-15° C. using cold water and crystallisation is completed by stirringfor at least another hour. The crystals are isolated using a suctionfilter dryer, the crystal slurry isolated is washed with 9 litres ofcold water (10-15° C.) and cold acetone (10-15° C.). The crystalsobtained are dried at 25° C. in a nitrogen current over a period of 2hours.

[0086] Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory).

[0087] The crystalline tiotropium bromide monohydrate thus obtained ismicronised by known methods in order to prepare the active substance inthe form of the average particle size corresponding to thespecifications according to the invention.

EXAMPLES OF FORMULATIONS

[0088] A) Inhalable powders: Ingredients μg per capsule 1) Tiotropiumbromide 21.7 Endothelin antagonist 2 270 Lactose 4708.3 Total 5000 2)Tiotropium bromide 21.7 Endothelin antagonist 2 450 Lactose 4528.3 Total5000 3) Tiotropium bromide × H₂O 22.5 Endothelin antagonist 2 495Lactose 4482.5 Total 5000 4) Tiotropium bromide 21.7 Endothelinantagonist 2 1400 Lactose 3578.3 Total 5000 5) Ipratropium bromide 40Endothelin antagonist 2 2000 Lactose 2960 Total 5000 6) Ipratropiumbromide 20 Endothelin antagonist 2 495 Lactose 4485 Total 5000 B)Propellant gas-containing aerosols for inhalation: Ingredients wt.-% 1)Suspension aerosol: Tiotropium bromide 0.015 Endothelin antagonist 21.2  Soya lecithin 0.3  TG 134a: TG227 = 2:3 ad 100 2) Suspensionaerosol: Ipratropium bromide 0.015 Endothelin antagonist 2 1.2  soyalecithin 0.3  TG 134a: TG227 = 2:3 ad 100 3) Suspension aerosol:Tiotropium bromide 0.029 Endothelin antagonist 2 1.4  Absolute ethanol0.5  Isopropyl myristate 0.1  TG 227 ad 100 4) Suspension aerosol:Ipratropium bromide 0.029 Endothelin antagonist 2 1.4  Absolute ethanol0.5  Isopropyl myristate 0.1  TG 227 ad 100

What is claimed is:
 1. A pharmaceutical composition of matter whichcomprises as active substance one or more anticholinergic substancescombined with as a second active substance one or more endothelinantagonists, wherein such anticholinergic substance and such endothelinantagonist may be in the form of an enantiomer, a mixture of enantiomersor in the form of a racemate, and further wherein the anticholinergicsubstance and such endothelin antagonist may be in the form of a solvateor a hydrate, all in combination with a pharmaceutically acceptableexcipient.
 2. The pharmaceutical composition of matter as recited inclaim 1 wherein the active substances are present in a singleformulation.
 3. The pharmaceutical composition of matter as recited inclaim 1 wherein the active substances are present in two separateformulations.
 4. The pharmaceutical composition of matter as recited inclaim 1 wherein the anticholinergic substance is a salt of tiotropium, asalt of oxitropium or a salt of ipratropium.
 5. The pharmaceuticalcomposition of matter as recited in claim 4 wherein the anticholinergicsubstance is the chloride, bromide, iodide, methane sulphonate orparatoluene sulphonate salt of tiotropium.
 6. The pharmaceuticalcomposition of matter as recited in claim 5 wherein the anticholinergicsubstance is tiotropium bromide.
 7. The pharmaceutical composition ofmatter as recited in claim 4 wherein the anticholinergic substance isthe chloride bromide, iodide, methane sulphonate or paratoluenesulphonate salt of oxitropium
 8. The pharmaceutical composition ofmatter as recited in claim 7 wherein the anticholinergic substance isoxitropium bromide.
 9. The pharmaceutical composition of matter asrecited in claim 4 wherein the anticholinergic substance is thechloride, bromide, iodide, methane sulphonate or paratoluene sulphonatesalt of ipratropium.
 10. The pharmaceutical composition of matter asrecited in claim 9 wherein the anticholinergic substance is ipratropiumbromide.
 11. The pharmaceutical composition of matter as recited inclaim 1 wherein the endothelin antagonist is selected from tezosentan,bosentan, enrasentan, sixtasentan, T-0201, BMS-193884, K-8794,PD-156123, PD-156707, PD-160874, PD-180988, S-0139 and ZD-1611.
 12. Thepharmaceutical composition of matter as recited in claim 11 wherein theendothelin antagonist is selected from tezosentan, bosentan, enrasentan,sixtasentan, T-0201 and BMS-193884.
 13. The pharmaceutical compositionof matter as recited in claim 1 wherein the weight ratio ofanticholinergic substance to endothelin antagonist is about 1:300 toabout 50:1.
 14. The pharmaceutical composition of matter as recited inclaim 13 wherein the weight ratio of anticholinergic substance toendothelin antagonist is about 1:250 to about 40:1.
 15. Thepharmaceutical composition of matter as recited in claim 1 suitable forinhalation.